Tuesday, November 23, 2010

In an apparent shift of position, the Boston Globe has parted company with much of the mainstream media by acknowledging the importance of gene patents to biotechnology, the potential deleterious impact if Judge Sweet's decision finding gene patents ineligible were to be upheld on appeal. The editorial points out that:

Whatever the principle at stake, one practical effect of Judge Sweet’s ruling, if it isn’t reversed, will be to eliminate part of the legal structure upon which the biotechnology industry was founded. The US might leave the company of Japan, Canada, Australia, and the European Union to become the biggest industrialized nation to consider a gene that’s been discovered, characterized, and isolated through scientific inquiry as categorically non-patentable.
. . .
There is still, of course, the very legitimate, and clearly urgent, question of whether gene patents serve the larger goal of advancing medical research and promoting the creation of therapies. But the best answer to this question is unlikely to arrive through a patent challenge. Determining the benefit to society of gene patents involves much more than just the narrow legal consideration of whether DNA isolated through the process of scientific discovery fits the definition of an invention under the US Patent Act.
. . .
Perhaps the best policy would be to simply do away with these patents. But the issue is of such magnitude that it would be best addressed outside the court system, by an act of Congress.

It is good to see that at least some in the mainstream media are waking up to the reality of what is at stake in the ACLU's challenge to gene patents.

On November 19, Regeneron sued Genentech in the US District Court for the Southern District of New York seeking a declaration that no activities relating to the Regeneron VEGF Trap infringe any claim of US patent numbers 5,952,199; 6,100,071; 6,383,486; 6,897,294; and 7,771,721 (all assigned to Genentech according to the complaint). The complaint is available here, compliments of PriorSmart.com.

Vascular Endothelial Growth Factor, or VEGF, is a protein growth factor which is required for formation of blood vessels, a process known as angiogenesis. According to Wikipedia:

In the adult human, angiogenesis is only consistently active in the gut - however in pathological cases such as cancer, where a solid tumor grows rapidly and therefore requires a blood supply, there is also active angiogenesis. Therefore, the blockade of VEGF is a potentially viable strategy for treating solid tumors.

Regeneron has developed a chimeric (i.e., fusion) protein, which it refers to as VEGF Trap (aflibercept), that comprises the extra-cellular domain of VEGF Receptor (the growth factor's natural receptor). The extra-cellular domain of the receptor is used to bind, or "trap" VEGF, and thereby keep it from binding receptors on the surface of blood vessels. Regeneron is working towards FDA approval to market VEGF Trap for a number of ophthalmologic and oncology indications. According to the complaint, the company intends to submit a Biologic License Application before the end of the second quarter of 2011 to market the product for a wet age-related macular degeneration. Yesterday, Regeneron stock rose 19.7% after the company announced positive Phase 3 clinical trial results for the drug (see here).

Genentech has developed an antibody called Avastin that binds VEGF. Avastin is already approved for the treatment of colon cancer. The five Genentech patents which are the subject of the declaratory judgment action are directed toward chimeric VEGF receptor proteins capable of binding VEGF.

Wednesday, November 10, 2010

Alnylam Pharmaceuticals is a biopharmaceutical company based in Cambridge, Massachusetts focused on developing synthetic "small interfering RNAs" (SiRNAs) as therapeutic agents. It has filed an amicus curiae brief in the Myriad gene patent case (AMP v. US PTO) that makes a number of insightful points, particularly in attempting to "debunk myths of Funk Brothers Seed Co. v. Kalo Inoculant Co."

Funk Brothers is generally assumed to be a case about patent eligibility. However, Alnylam points out that Funk Brothers was decided by the Supreme Court in 1948, prior to the enactment of the 1952 patent statute and thus prior to 35 USC 101, which is the statutory basis for the patent eligibility doctrine. Prior to 1952, the Court used the term “invention” to refer to "inventiveness," a concept that subsequent to 1952 and the enactment of 35 USC 103 we refer to as "nonobviousness." The Court in Funk Brothers found the claimed subject matter was not the “product of invention,” but Alnylam argues that post-1952 this statement should be interpreted a finding of obviousness, not patent ineligibility.

I have always found it extremely difficult, if not impossible, to find a principled distinction between the inventions claimed in Funk Brothers and Diamond V. Chakrabarty that would justify finding only Dr. Chakrabarty's invention patent eligible. In Funk Brothers, the alleged invention was a novel and useful combination, in a single inoculant, of naturally occurring microorganisms in a combination that did not exist naturally. Chakrabarty’s invention was a novel and useful combination, in a single microorganism, of naturally occurring plasmids in a combination that did not exist naturally. It is important to bear in mind that Chakrabarty's invention did not involve any genetic engineering at the molecular level.

In Funk Brothers, it has been pointed out that while the combination of bacteria in a single inoculant was novel, the bacteria function in the same manner and have the same characteristics as they would have in nature. But the same can be said regarding the plasmids Dr. Chakrabarty introduced into a single microorganism. These were naturally occurring plasmids, and in the claimed microorganism they encoded the exact same proteins, and performed the exact same function as they did in their natural state.

In a nutshell, Funk Brothers was a novel combination of naturally occurring bacteria capable of achieving novel and useful function, with the bacteria functioning in the same manner as they do in nature. Chakrabarty was a novel combination of naturally occurring plasmid DNA capable of achieving novel and useful function, with the plasmid DNA functioning in the same manner as they do in nature. I don't see how one invention can be patent eligible and the other not. However, if Funk Brothers was really decided based on obviousness rather than patent eligibility, as argued by Alnylam, the two decisions are easily reconciled.

Friday, November 5, 2010

I can understand why many people find the position advanced by the US government in AMP v. PTO (the DOJ amicus brief, discussed in an earlier post) quite appealing. On its face, it seems to offer a reasonable compromise: patent eligibility for "engineered" cDNA, but not for genomic DNA merely "excised" from a human chromosome. However, the distinction is superfical, and does not in my view withstand closer scrutiny.

In particular, the DOJ conveniently ignores the fact that in almost all cases isolation of genomic DNA involves amplification, either through laboratory techniques such as PCR, or by replication in recombinant cells. This distinguishes DNA and RNA from other biomolecules. Prior to the development of recombinant molecular biology in the 1970s, isolation of a naturally occurring biomolecule, such as a protein, involved removing the biomolecule produced in a naturally occurring from other biological constituents. Importantly, all of the purified biomolecule originated in the natural source, and was purified by separating it from other cellular constituents.

In contrast, because DNA can serve as a template for its own replication, DNA is normally isolated by amplifying it many times ("million-fold" is the term used in the amici brief filed by BIO and AUTM). As a result, a typical preparation of "isolated genomic DNA" actually consists primarily of synthetic copies of the genomic DNA molecule.

The DOJ makes much of the fact that a cDNA molecule does not contain the introns, which exist in most human genes, and implies that molecular biologists have "engineered" the introns out. In fact, the introns are naturally removed in the body when genomic DNA is transcribed into mRNA. There is no human engineering involved; production of a cDNA molecule simply entails making a DNA copy of a naturally occurring mRNA and then amplifying it.

In most instances a preparation of isolated genomic DNA comprises synthetic DNA molecules, produced in the laboratory by amplification, that correspond in sequence to a naturally occurring genomic DNA. A preparation of cDNA comprises synthetic DNA molecules, produced in the laboratory by amplification, that correspond in sequence to a naturally occurring mRNA. Considered in this light, I think that the distinction DOJ makes between "excised" genomic DNA versus "engineered" cDNA proves largely illusory.

True, a cDNA molecule has a slightly different chemical structure than the mRNA on which it is based, but the differences are small. The sugar group (ribose) in DNA is lacking an oxygen atom (hence the “deoxy”), and one of the four base groups in RNA (uracil) is slightly different than the corresponding base in DNA (thymine), due to replacement of a methyl group with a hydrogen atom. But mRNA and its corresponding cDNA both encode the same information, and both hybridize to the same complementary strand.

In many instances, a synthetic copy of a genomic DNA molecule is also chemically different from the original. Most naturally occurring genomic DNA is methylated, a form of epigenetic modification, while synthetic copies are often not methylated.

In short, the minor structural difference between cDNA and mRNA is not so qualitatively different than the difference between amplified genomic DNA and genomic DNA of natural origin to warrant using this distinction as the basis for drawing a line between patent eligible and patent ineligible subject matter.

Thursday, November 4, 2010

Today I published a short article in Managing IP "discerning" Myriad's patent claims, currently under attack in AMP v. PTO . The article is available here for subscribers to Managing IP, along with other materials relating to the Myriad case.

The substance of my article is as follows:

As a preliminary matter, it bears noting that the precise contours of Myriad's patent claims are not entirely clear. Claim interpretation is a notoriously unpredictable exercise, and no court has ever formally construed the claims, or considered their scope in the context of infringement litigation. In fact, no US court has ever interpreted a human gene patent claim in a case involving genetic diagnostic testing. In an amicus brief filed with the Federal Circuit in AMP v. PTO, the author (Holman) and Robert Cook-Deegan explain that if the claims were ever enforced in an infringement suit there are reasons to believe that the claims would not be interpreted as broadly as many critics of gene patents have assumed. The following analysis is based on a facial reading of the claims in view of the patent specifications, as well as statements made by the district court and by Myriad.

The challenged patent claims recite subject matter falling under general three categories: isolated DNA molecules claimed as compositions of matter, methods of diagnostic testing, and cell-based assay methods. Importantly, none of the claims encompass DNA as it exists naturally in the human body, and none of the claims recite mere genetic information. Thus, popular allegations that the patent claims confer ownership on people's bodies, or can be used to prevent a doctor from communicating the existence of a genetic predisposition to cancer to a patient, would appear to be unfounded.

Isolated DNA claimsAll of the composition of matter claims are limited to "isolated" DNA molecules, and hence clearly do not encompass genomic DNA as it exists naturally in the human body. This is consistent with long-standing patent office policy which requires claims directed to naturally occurring DNA molecules to be limited to isolated, purified and/or recombinant embodiments of the molecule, in order to prevent the patent from covering native genes in the human body

There is, however, some uncertainty with respect to exactly how broadly the term "isolated" should be interpreted. Myriad's patent specifications define the term to encompass any DNA sequence that has been “removed from its naturally occurring environment, and includes recombinant or cloned DNA isolates and chemically synthesized analogs or analog biologic synthesized by heterologous systems." Many in the biotechnology community have assumed that claims to "isolated" DNA molecules broadly encompass the claimed sequence in any context outside its native environment, such as residing in a recombinant DNA vector, cell or organism. However, there is little US case law directly addressing the proper interpretation of the term "isolated" in this context, and there is reason to believe that if litigated the term might be given a narrower construction, at least in some cases (depending, for example, on how the term "isolated" is used in the patent specification and in communications to the patent office during patent prosecution).

Some of the composition of matter claims encompass any isolated DNA that codes for a full length BRCA1 or BRCA2 protein. These claims are relatively broad in the sense that they would appear to cover any of the astronomical number of redundant DNA sequences that would encode the BRCA1 protein. They also arguably cover genomic DNA coding for the protein, i.e., the isolated gene as it exists in the human body. Assuming the courts gives the term "isolated" an expansive reading, the claims arguably cover very large recombinant molecules that comprise the BRCA coding sequence (i.e., large DNA vectors), as well as recombinant cells or organisms comprising the coding sequence in a non-native context.

Although many have assumed that claims directed towards DNA encoding full-length BRCA proteins can be used to block genetic diagnostic testing, in fact these claims would not appear to be infringed by standard genetic diagnostic testing. In conventional BRCA diagnostic testing, segments of the BRCA gene are amplified and sequenced, not the entire full-length genomic sequence. As a consequence, the full-length coding sequence is not made or used, and thus there would seem to be no infringement (see Holman/Cook-Deegan amici brief). The claim would however appear to cover a recombinant DNA molecule encoding a full-length BRCA protein, which could be used in drug discovery research or, potentially, gene-based therapy.

There are also a variety of narrower isolated DNA claims at issue. For example, some of the isolated DNA claims are limited to a specific cDNA molecule encoding a BRCA protein. These claims are relatively narrow, and could be readily circumvented in many instances by simply using a different DNA sequence that encodes the same protein (which is trivial given the redundancy of the genetic code and the general availability of whole gene synthesis). Although the district court found the cDNA claims patent ineligible, the government argues in its amicus brief that while isolated genomic DNA is patent ineligible, cDNA is patent eligible because it does not exist in nature (cDNA is essentially a DNA version of a naturally existing RNA molecule).

Some of the claims recite any isolated DNA having least 15 nucleotides of a DNA sequence encoding full-length BRCA protein. These claims appear on their face to be extremely broad, encompassing conventional BRCA genetic diagnostic testing (because the testing involves amplification of fragments of the BRCA gene exceeding 15 nucleotides in length). However, a recent bioinformatics study suggests that the breadth of these claims could render them invalid based on anticipation by genetic sequences published in GenBank more than one year before the patents’ filing dates (see Holman/Cook-Deegan amici brief).
Method of diagnosis claimsThe method of diagnosis claims are generally directed towards processes of "analyzing" a person's BRCA gene sequence for the existence of a naturally occurring mutation or genetic variation, or “comparing” two BRCA sequences in order to identify the existence of a variation. Critics of gene patents have argued that these method claims broadly cover the mere mental process of analyzing or comparing genetic sequence information, and this was the interpretation of the district court in its summary judgment opinion. However, in their appellant brief Myriad argues for a narrower interpretation, explaining that when the claims are read in light of the specification it is clear that the claims require "extracting, processing and analyzing” DNA molecules, not merely an analysis or comparison of genetic information.

The scope of these method claims could be significant. For example, in the not-too-distant future it is predicted that many people will have their whole genome sequenced. With this information in hand, one could then look for medically significant genetic variations, such as variations in the BRCA gene. Under the district court's broad interpretation, the method claims might be infringed by a doctor or patient merely analyzing the genetic information, which is one of the fears voiced by critics of gene patents. On the other hand, under Myriad's proposed interpretation merely analyzing genetic information would not constitute infringement.

Cell-based assay methodsOne of the challenged patent claims recite a method of using recombinant cells engineered to express a BRCA protein to screen for potential cancer drugs. This claim clearly has no implications for genetic testing, and it is unclear why the ACLU chose to challenge its patent eligibility.

Monday, November 1, 2010

On Friday I thought I posted links to amicus briefs filed by Holman/Cook-Deegan and DOJ in AMP v. PTO, but turns out they were not operational, I believe the problem has been corrected. Just in case, the link to Holman/Cook-Deegan brief is here. Please let me know if still not working (they work on my computer).

About Me

I am a law professor at the University of Missouri-Kansas City School of Law. My primary research interests lie at the intersection of biotechnology and intellectual property. This blog provides analysis and commentary on recent developments relevant to this area of the law.